Highlights from Recent Cancer Literature
Journal: Cancer Research (2012)

Lund AW, Duraes FV, Hirosue S, Raghavan VR, Nembrini C, Thomas SN, et al. VEGF-C promotes immune tolerance in B16 melanomas and cross-presentation of tumor antigen by lymph node lymphatics. Cell Reports 2012; doi:10.1016/j.celrep.2012.01.005.Lymphatics play an important role in cancer spread, and tumors that express the lymphangiogenic factor VEGF-C are more metastatic and have a worse prognosis. Lund and colleagues suggest that lymphatics that drain cancers may also have an active protumor role, inducing immune tolerance to cancer-associated antigens. They describe how VEGF-C, and the lymphangiogenesis that it promotes, can cause deletion of tumorspecific CD8+ cytotoxic T cells or leave them "functionally exhausted" by the time they reach the tumor. Using B16-melanoma cells expressing VEGF-C and chicken ovalbumin (OVA) as a model tumor antigen, Lund and colleagues found that, whereas VEGF-C expression did not affect growth of the original tumor, VEGF-C–expressing tumors contained more immunosuppressive regulatory T cells and fewer antigen-specific CD8+ T cells than did tumors with low VEGF-C. Vaccines against OVA did not work in tumors expressing VEGF-C; the VEGF-C was promoting local deletion of OVA-specific CD8+ cells. This was because lymphatic endothelial cells in the draining lymph nodes cross-presented the tumor antigen to OVA-specific CD8+ T cells, driving their proliferation and then apoptosis. In support of these findings, a VEGF-C antagonist increased the efficacy of vaccination and suppressed tumor growth. The implication of these findings is that targeting tumor-associated lymphatics or VEGF-C may increase the efficacy of existing cancer vaccines and other cancer immunotherapies.Pei Y, Moore CE, Wang J, Tewari AK, Eroshkin A, Cho YJ, et al. An animal model of MYC-driven medulloblastoma. Cancer Cell 2012;21:155–67.Kawauchi D, Robinson G, Uziel T, Gibson P, Rehg J, Gao C, et al. A mouse model of the most aggressive subtype of human medulloblastoma. Cancer Cell 2012;21:168–80.Medulloblastomas are primitive neuroectodermal tumors involving the cerebellum and posterior fossa that most often affect children and young adults. Current treatments cure only a subset of patients and result in significant long-term morbidity. Recent gene expression studies point to 4 major molecular subtypes, leading to a goal of matching targeted therapeutics to individual expression-defined subtypes. Among the 4 subtypes, one appears driven by WNT signaling and a second by signaling from the sonic hedgehog (SHH) pathway. Group 3 is associated with amplification/overexpression of the MYC oncogene, and the fourth group overexpresses genes associated with neuronal differentiation. The development of mouse models that faithfully represent these subclasses would be of value for understanding subclass-dependent biology as well as preclinical therapeutics. To date, mouse models representing the WNT and SHH pathways have been reported. Models for the remaining 2 subtypes are needed, perhaps most urgently for the MYC subtype, because this subtype is associated with anaplastic histology, poor response to therapy, and unfavorable patient outcome. Two recent reports describe the development of mouse models for the MYC-driven subtype. Pei and colleagues describe a model based on isolation of cells from postnatal murine cerebellum that are positive for Prominin1 (mouse equivalent of CD133) and also lack expression of glial and neuronal lineage markers. They introduce a mutationally stabilized allele of MYC. Whereas elevated MYC expression led to increased cell proliferation and self-renewal in vitro, MYC alone was insufficient for tumor formation in vivo (cerebella of immunocompromised mice). Because tumor cell apoptosis was identified following injection of these cells, the authors introduced a dominant negative allele of TP53 (DNp53). The combination of the mutant MYC and DNp53 alleles led to abrogation of the apoptotic phenotype and resultant tumor formation. Importantly, the tumors showed the large-cell anaplastic pathology, which is similar to that of human MYC-driven medulloblastoma. Using a conditional MYC construct, they showed that continuous MYC expression was required for tumor formation. Gene expression profiling showed similarities of their model to human group 3 medulloblastoma tumors and implicated the phosphoinositide 3-kinase (PI3K) pathway in this model by showing that BEZ-235 (an antagonist of both PI3K and mTOR) and BKM-120 (an antagonist of PI3K), led to decreased tumor cell proliferation and tumorigenesis. Kawauchi and colleagues used a similar strategy, transducing MYCN or MYC into cultured cells from Trp53 null mice and sorting granule neuronal precursors using Atoh1. Granule neural precursors are driven by SHH, and MYCN-driven tumors (following injection of these cells into immunocompromised mice) were SHH positive with classical features. Surprisingly, however, MYC-driven tumors were negative for SHH and had anaplastic features. The MYC-driven tumors were insensitive to SHH pathway inhibitors—a relevant finding because these inhibitors are entering clinical trials in unselected medulloblastoma patients without subtype discrimination. Transcriptomal analysis showed consistencies with the human group 3 tumors. Although cells had not been previously sorted by Prom1, the resulting MYC tumors showed overexpression of this and other stem cell markers. These findings raise questions about cells of origin and suggest the possibility of a stem cell origin or instead, that MYC induces progenitor or tumor cells to acquire stem-like properties. Together, these studies offer new tools for preclinical testing of the most aggressive medulloblastoma subtype and extend our understanding of the molecular subclassification of this tumor type.Yuneva MO, Fan TW, Allen TD, Higashi RM, Ferraris DV, Tsukamoto T, et al. The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell Metab 2012;15:157–70.The altered cellular metabolism of glucose and glutamine in cancer has received recent attention as a mechanism that can be exploited for therapeutic intervention. However, how oncogenic insults affect metabolism of these key nutrients has been analyzed primarily in cell culture models. In this study, Yuneva and colleagues used stable isotope-based metabolic analysis to evaluate how Myc- and Met-driven liver tumors as well as Myc-driven lung tumors alter cellular metabolism in vivo. The authors identified striking oncogene-specific and tissue-specific metabolic changes. Remarkably, Myc-induced liver tumors substantially increased glucose and glutamine uptake and catabolism as well as lactate production relative to normal liver tissue, whereas Met-induced liver tumors did not. These effects can be explained partially by the differential expression of key enzymes driving the transport and metabolism of glucose and glutamine metabolism observed between Myc- and Met-driven liver tumors. Similar to Myc-induced liver tumors, Myc-induced lung tumors display increased glucose catabolism to lactate. However, in contrast to Myc-driven liver tumors, Myc-driven lung tumors displayed increased expression of glutamine synthetase and had high levels of intracellular glutamine. These findings underscore important tissue-specific roles for Myc in glutamine metabolism, suggesting that therapeutics that target enzymes of the glutamine catabolism machinery may be efficacious in Myc-driven cancers.Stagg J, Beavis PA, Divisekera U, Liu MC, Moeller A, Darcy PK, et al. CD73-deficient mice are resistant to de novo tumorigenesis. Cancer Res; Published OnlineFirst March 6, 2012; doi:10.1158/0008-5472.CAN-12-0420.CD73, a cell surface enzyme, is frequently upregulated in various human and mouse cancers and implicated in the control of tumor progression by suppressing the immune response. By upregulating CD73, tumor cells can accumulate extracellular adenosine and remarkably create a barrier against antitumor immunity and further can suppress tumor-targeting T-cell function. Although an involvement of CD73 in tumor progression has been suggested in various cancers, its precise role in tumor cell initiation and progressive development of the cancerous state remains largely unknown. Stagg and colleagues have examined the role of CD73 in prevention and promotion of tumorigenesis in 3-methylcholanthrene (MCA)-induced fibrosarcoma (C57BL/6), and a transgenic (TRAMP) prostate cancer model with both wild-type and CD73−/− background. Remarkably, the CD73−/− mice were resistant to MCA-induced tumor initiation, which appeared to be mediated by CD8+ T cells based on the observation that depletion of CD8+ T cells in the established tumors completely abrogated the protective activity of CD73 deficiency. Similarly, in the CD73−/− TRAMP mice, prostate tumor growth was significantly inhibited, which was associated with increased homing of CD8+ and CD4+ T cells into the tumor bed. Moreover, anti-CD73 monoclonal antibody treatment delayed TRAMP-C1 cell line–derived in vivo tumor growth in a CD8+ T-cell–dependent manner. This study provides compelling evidence for a definitive role of CD73 upregulation in tumor initiation and cancer progression, and accordingly, CD73 may serve as a therapeutic target for treating various cancers.Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, et al. IDH mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 2012 Feb 15 [Epub ahead of print].Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 2012 Feb 15 [Epub ahead of print].Tumor types, including glioblastoma, that exhibit the CpG island methylator phenotype (CIMP) represent tumor subsets with stereotypic epigenomic aberrations and distinct biologic and clinical behaviors. Glioma CIMP (G-CIMP) was recently discovered in an analysis of data from The Cancer Genome Atlas (TCGA), but the molecular basis of G-CIMP is unclear. What is clear from TCGA data is a tight positive correlation of G-CIMP with mutations in IDH1. IDH1 mutations in gliomas are nearly all at codon 132, altering the enzymatic properties that promote the formation of 2-hydroxyglutarate (2HG), instead of α-ketoglutarate. This correlation raised the question as to which came first. Does acquisition of G-CIMP create an environment favorable for IDH mutation, or is it the other way around? Turcan and colleagues show that IDH mutation is likely to be the initiating event. These authors engineered mutant IDH1 protein (R132H) and introduced the cDNA into primary human astrocytes. The cells exhibited altered histone marks and global alterations in the methylome. A comparison of methylation marks and gene expression signatures in cultured cells with changes found in human gliomas revealed significant similarities, suggesting a direct causal link between IDH1 mutation and G-CIMP. Turcan and colleagues show that mutant IDH1 protein resulted in decreased TET2-dependent 5-hydroxymethylcytosine (5hmC) levels. Because 5hmC is a primary mechanism used by cells for DNA demethylation, inhibition of TET2 (an α-ketoglutarate-dependent DNA demethylase) in the setting of IDH1 mutation accounts for increased DNA methylation, ultimately leading to a CIMP pattern. In a companion article, Lu and colleagues show that IDH mutation, by impairing histone demethylation, represses lineage-specific cell differentiation and correlates marks in histone H3K9 with increased DNA methylation in cultured cells. These authors show that the H3Kp demethylase KDM4C/JMJD2C removed histone H3 methylation marks and was inhibited by 2HG in a dose-dependent manner. Lu and colleagues further show that knockdown of KDM4C/JMJD2C resulted in a loss of differentiation, suggesting that IDH mutation, via increased 2HG, promotes the dedifferentiated state. Administration of a-ketoglutarate reversed these effects. Overall, the findings reported in these articles provide a mechanistic link that accounts for the tight correlation of the mutations in IDH1 and IDH2 with acquisition of CIMP and link changes in cellular metabolism with epigenetic state.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.